Piezo1 is required for outflow tract and aortic valve development.

Area of Science:

• Cardiovascular biology
• Developmental biology
• Molecular genetics

Background:

• Hemodynamic forces during embryogenesis influence cardiovascular development.
• Mechanosensory systems detect these forces, promoting cardiogenesis.
• PIEZO1, a mechanosensitive ion channel in endothelial cells, is a candidate for sensing these forces.

Purpose of the Study:

• To investigate the role of PIEZO1 in outflow tract and aortic valve development.
• To determine if PIEZO1 is required for normal cardiac development.

Main Methods:

• Analysis of heart development in zebrafish.
• Assessment of PIEZO1 expression in the developing outflow tract.
• Disruption of Piezo1 signaling in zebrafish.
• Genomic data analysis of patients with left ventricular outflow tract obstructions (LVOTO).
• In vitro and in vivo assays of PIEZO1 variants.

Main Results:

• Piezo1 is expressed in the developing zebrafish outflow tract and detects hemodynamic forces.
• Disrupting Piezo1 signaling results in defective outflow tract and aortic valve development.
• Potentially pathogenic PIEZO1 variants were identified in patients with LVOTO.
• These variants act as dominant negatives, inhibiting PIEZO1 mechanosensory activity.
• Expression of dominant-negative PIEZO1 variants in zebrafish causes aortic valve defects.

Conclusions:

• The mechanosensitive ion channel PIEZO1 is crucial for outflow tract and aortic valve development.
• PIEZO1 dysfunction may contribute to the etiology of congenital heart diseases like LVOTO.